Murase Akio, Taniguchi Yasuhito, Tonai-Kachi Hiroko, Nakao Kazunari, Takada Junji
Pfizer Global Research and Development, Discovery Biology Research, Aichi, Japan.
Life Sci. 2008 Jan 16;82(3-4):226-32. doi: 10.1016/j.lfs.2007.11.002. Epub 2007 Nov 22.
Activation of the prostaglandin E(2) (PGE(2)) EP(4) receptor, a G-protein-coupled receptor (GPCR), results in increases in intracellular cyclic AMP (cAMP) levels via stimulation of adenylate cyclase. Here we describe the in vitro pharmacological characterization of a novel EP(4) receptor antagonist, CJ-042794 (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl)oxy]phenyl}carbonyl)amino]ethyl}benzoic acid). CJ-042794 inhibited [(3)H]-PGE(2) binding to the human EP(4) receptor with a mean pK(i) of 8.5, a binding affinity that was at least 200-fold more selective for the human EP(4) receptor than other human EP receptor subtypes (EP(1), EP(2), and EP(3)). CJ-042794 did not exhibit any remarkable binding to 65 additional proteins, including GPCRs, enzymes, and ion channels, suggesting that CJ-042794 is highly selective for the EP(4) receptor. CJ-042794 competitively inhibited PGE(2)-evoked elevations of intracellular cAMP levels in HEK293 cells overexpressing human EP(4) receptor with a mean pA(2) value of 8.6. PGE(2) inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNFalpha) in human whole blood (HWB); CJ-042794 reversed the inhibitory effects of PGE(2) on LPS-induced TNFalpha production in a concentration-dependent manner. These results suggest that CJ-042794, a novel, potent, and selective EP(4) receptor antagonist, has excellent pharmacological properties that make it a useful tool for exploring the physiological role of EP(4) receptors.
前列腺素E2（PGE2）的EP4受体是一种G蛋白偶联受体（GPCR），其激活可通过刺激腺苷酸环化酶使细胞内环磷酸腺苷（cAMP）水平升高。在此，我们描述了一种新型EP4受体拮抗剂CJ-042794（4-{(1S)-1-[({5-氯-2-[(4-氟苯基)氧基]苯基}羰基)氨基]乙基}苯甲酸）的体外药理学特性。CJ-042794抑制[3H]-PGE2与人EP4受体的结合，平均pK(i)为8.5，其结合亲和力对人EP4受体的选择性比对其他人EP受体亚型（EP1、EP2和EP3）至少高200倍。CJ-042794对包括GPCR、酶和离子通道在内的另外65种蛋白质未表现出任何显著结合，这表明CJ-042794对EP4受体具有高度选择性。CJ-042794竞争性抑制过表达人EP4受体的HEK293细胞中PGE2诱导的细胞内cAMP水平升高，平均pA(2)值为8.6。PGE2抑制人全血（HWB）中脂多糖（LPS）诱导的肿瘤坏死因子α（TNFα）产生；CJ-042794以浓度依赖性方式逆转PGE2对LPS诱导的TNFα产生的抑制作用。这些结果表明，CJ-042794是一种新型、强效且选择性的EP4受体拮抗剂，具有出色的药理学特性，使其成为探索EP4受体生理作用的有用工具。
